Infection with the hepatitis B virus (HBV) can lead to chronic hepatitis and hepatocellular carcinoma. Current therapies for chronic HBV infection are only moderately effective, and are limited by severe side effects and viral resistance. Thus, there remains a need for new therapies for this serious disease. The liver injury associated with HBV infection is primarily caused by the CD8 T cell response to the virus. The interferon (IFN)-3-mediated noncytopathic inhibition of HBV is an important component of the host innate immune response to the virus, as it reduces virus replication without damaging the infected hepatocytes. However, relatively little is known about how the immune response to HBV is regulated by other host cytokines. IFN-3 belongs to the class II 1-helical cytokine family, which also includes IFN-1/2, the IFN-related proteins (IL-28A/B, IL-29), and the IL-10 family cytokines (IL-10, 19, 20, 22, 24, and 26). The IL-22 receptor is expressed on hepatocytes, and this cytokine displays immunomodulatory and protective properties in the liver and other tissues. We will examine the hypothesis that IL-22 plays an important role in the innate and adaptive host immune responses to HBV. Our general approach will be to use cell culture and transgenic mouse models of HBV replication to study the influence of IL-22 on virus replication, cellular gene expression, and inflammation after viral antigen recognition in the liver. These experiments are important, as they may identify IL-22 as a new host factor that limits HBV persistence and disease. A complete understanding of these processes may also lead to improved cytokine-based therapies for chronic HBV, which would have the potential to prevent hepatocellular carcinoma. PUBLIC HEALTH RELEVANCE: Chronic hepatitis B virus (HBV) infection is associated with liver cirrhosis and hepatocellular carcinoma, and causes over a million deaths each year worldwide. We will examine the hypothesis that IL-22, a recently characterized IL-10-related cytokine, protects the liver from HBV- associated injury. A complete understanding of the role of this cytokine in the immune response to HBV may lead to improved therapies for chronic HBV.